Solid forms of [4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl-[5-methanesulfonyl-2-((s)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone

ABSTRACT

The present invention relates to four distinct crystalline forms and to an amorphous form of [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone, and to their use in the preparation of pharmaceutical compositions. The compounds of present invention are suitable for the treatment of psychoses, pain, neurodegenerative disfunction in memory and learning, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer&#39;s disease.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06127269.6 filed Dec. 28, 2006, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonehas been already described in published PCT patent application No. WO2005/014563.

SUMMARY OF THE INVENTION

The present invention provides four distinct crystalline forms and to anamorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone,and to their use in the preparation of pharmaceutical compositions.

The four distinct crystalline forms and amorphous form of4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneare suitable for preparing a pharmaceutical formulation.

In a first aspect, the present invention relates to three distinctcrystalline forms A, B and C of the following compound:

In another aspect, the present invention relates to the amorphous formof[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

In another aspect, the present invention relates to a methylparabencocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising a crystalline form A, B, C or an amorphous formor a methylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneas an active ingredient.

In still a further aspect, the invention relates to a method for thetreatment of treating psychoses, pain, neurodegenerative disfunction inmemory and learning, schizophrenia, dementia and other diseases in whichcognitive processes are impaired, such as attention deficit disorders orAlzheimer's disease which comprises administering a therapeuticallyeffective amount of a crystalline form A, B, C or an amorphous form or amethylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

The aforementioned solid forms can be distinguished by physical andchemical properties that can be characterized by infra-red spectra,X-ray powder diffraction patterns, melting behavior or glass transitiontemperatures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: shows a XRPD (Powder X-Ray Powder Diffraction) pattern of atypical lot of form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 2: shows an IR (Infra Red Spectroscopy) spectrum of a typical lotof form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 3: shows a DSC (Differencial Scanning Calorimetry) curve of atypical lot of form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 4: shows a TGA (Thermo Gravimetric Analysis) curve of a typical lotof form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 5: shows a XRPD (Powder X-Ray Diffraction) pattern of a typical lotof form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 6: shows an IR (Infra Red) spectrum of a typical lot of form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 7: shows a DSC (Differencial Scanning Calorimetry) curve of atypical lot of form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 8: shows a TGA (Thermo Gravimetric Analysis) curve of a typical lotof form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 9: shows a XRPD (Powder X-Ray Diffraction) pattern of a typical lotof form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 10: shows an IR (Infra Red) spectrum of a typical lot of form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 11: shows a DSC (Differencial Scanning Calorimetry) curve of atypical lot of form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 12: shows a TGA (Thermo Gravimetric Analysis) curve of a typicallot of form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 13: shows a XRPD (Powder X-Ray Diffraction) pattern of a typicallot of the amorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 14: shows an IR (Infra Red) spectrum of a typical lot of theamorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 15: shows DSC (Differencial Scanning Calorimetry) curves of twotypical lots of the amorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 16: shows a TGA (Thermo Gravimetric Analysis) curve of a typicallot of the amorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 17: shows a DVS (Dynamic Vapor Sorption) isotherm of a typical lotof the amorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 18: shows a XRPD (Powder X-Ray Diffraction) pattern of a typicallot of the methylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-A]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 19: shows an IR (Infra Red) spectrum of a typical lot of themethylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 20: shows a DSC (Differencial Scanning Calorimetry) curve of atypical lot of the methylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

FIG. 21: shows a TGA (Thermo Gravimetric Analysis) curve of a typicallot of the methylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “amorphous forms” or “amorphous” denotes a material thatlacks long range order and as such does not show sharp X-ray peaks, i.e.a Bragg diffraction peak. The XRPD pattern of an amorphous material ischaracterized by one or more amorphous halos.

Bragg's law describes the diffraction of crystalline material with theequation:

2d sin theta=n lambda

wherein d=perpendicular distance between pairs of adjacent planes in acrystal (d-spacing), theta=Bragg angle, lambda=wavelength and n=integer.

When Bragg's law is fulfilled, the reflected beams are in phase andinterfere constructively so that Bragg diffraction peaks are observed inthe X-ray diffraction pattern. At angles of incidence other than theBragg angle, reflected beams are out of phase and destructiveinterference or cancellation occurs. Amorphous material does not satisfyBragg's law and no Bragg diffraction peaks are observed in the X-raydiffraction pattern.

“An amorphous halo” is an approximately bell-shaped diffraction maximumin the X-ray powder diffraction pattern of an amorphous substance. TheFWHM of an amorphous halo is bigger than two degrees in 2-theta.

“FWHM” means full width at half maximum, which is a width of a peakappearing in an XRPD pattern at its half height.

“API” is used herein as an acronym of Active Pharmaceutical Ingredient.

“DSC” is used herein as an acronym of Differencial Scanning Calorimetry.DSC curves were recorded using a Mettler-Toledo™ differential scanningcalorimeter DSC820 or DSC 821 with a FRS05 sensor. System suitabilitytests and calibrations were carried out according to the internalstandard operation procedure.

For the measurements of crystalline forms approximately 2-6 mg of samplewere placed in aluminum pans, accurately weighed and hermetically closedwith perforation lids. Prior to measurement, the lids were automaticallypierced resulting in approx. 1.5 mm pin holes. The samples were thenheated under a flow of nitrogen of about 100 mL/min using heating ratesof 10 K/min.

For the measurements of amorphous forms, approximately 2-6 mg of samplewere placed in aluminum pans, accurately weighed and hermeticallyclosed. The samples were then heated under a flow of nitrogen of about100 mL/min using heating rates of 10 K/min.

“DVS” is used herein as an acronym of Dynamic Vapor Sorption. DVSisotherms were collected on a DVS-1 (SMS Surface Measurements Systems)moisture balance system. The sorption/desorption isotherms were measuredstepwise in a range of 0% R H to 90% RH at 25° C. A weight change of<0.002 mg/min was chosen as criterion to switch to the next level ofrelative humidity (with a maximum equilibration time of six hours, ifthe weight criterion was not met). The data were corrected for theinitial moisture content of the samples; that is, the weight afterdrying the sample at 0% relative humidity was taken as the zero point.

“Form A” is used herein as abbreviation for the crystalline form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

“Form B” is used herein as abbreviation for the crystalline form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

“Form C” is used herein as abbreviation for the crystalline form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

“Methylparaben cocrystal form” is used herein as abbreviation for themethylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

“IR” is used herein as an acronym of Infra Red, hence “IR spectrum”means Infra Red Spectrum. The IR-spectrum of the sample was recorded asfilm of a Nujol suspension consisting of approx. 5 mg of sample and fewNujol between two sodium chloride plates, with an FT-IR spectrometer intransmittance. The Spectrometer was a Nicolet™ 205XB or equivalent(resolution: 2 cm⁻¹, 32 or more coadded scans, MCT detector).

“XRPD” is used herein as an acronym of X-Ray Powder Diffraction. X-raydiffraction patterns were recorded at ambient conditions in transmissiongeometry with a STOE STADI P diffractometer (Cu Kα radiation, primarymonochromator, position sensitive detector, angular range 3 to 42 2Theta(deg), approximately 60 minutes total measurement time). The sampleswere prepared and analyzed without further processing (e.g. grinding orsieving) of the substance.

Alternatively, X-ray diffraction patterns were recorded in transmissiongeometry with a STOE STADIP diffractometer with Cu Kα radiation (1.54 Å)and a position sensitive detector. The samples (approximately 50 mg)were prepared between thin polymer (or aluminum) films and analyzedwithout further processing (e.g. grinding or sieving) of the substance.

X-ray diffraction patterns were also measured on a Scintag X1 powderX-ray diffractometer equipped with a sealed copper Kα 1 radiationsource. The samples were scanned from 2 to 36 2 Theta (deg) at a rate of1 degree 2 Theta per minute with incident beam slit widths of 2 and 4 mmand diffracted beam slit widths of 0.3 and 0.2 mm.

For single crystal structure analysis a single crystal was mounted in aloop on a goniometer and measured at ambient conditions. Alternatively,the crystal was cooled in a nitrogen stream during measurement. Datawere collected on a STOE Imaging Plate Diffraction System (IPDS) fromSTOE (Darmstadt). In this case Mo-radiation of 0.71 Å wavelength wasused for data collection. Data was processed with STOE IPDS-software.The crystal structure was solved and refined with standardcrystallographic software. In this case the program ShelXTL from BrukerAXS (Karlsruhe) was used.

Alternatively, for synchrotron radiation was used for data collection. Asingle crystal was mounted in a loop and cooled to approximately 100 Kin a nitrogen stream. Data was collected at the Swiss Light Sourcebeamline X10SA using a MAR CCD225 detector with synchrotron radiationand data processed with the program XDS. The crystal structure wassolved and refined with standard crystallographic software. In this casethe program ShelXTL from Bruker AXS (Karlsruhe) was used. The crystalstructure was solved and refined with ShelXTL (Bruker AXS, Karlsruhe)

“TGA” is used herein as an acronym of Thermo Gravimetric Analysis. TGAcurves were measured on a Mettler-Toledo™ thermogravimetric analyzer(TGA850 or TGA851). System suitability tests and calibrations werecarried out according to the internal standard operation procedure.

For the thermogravimetric analyses, approx. 5 to 10 mg of sample wereplaced in aluminum pans, accurately weighed and hermetically closed withperforation lids. Prior to measurement, the lids were automaticallypierced resulting in approx. 1.5 mm pin holes. The samples were thenheated under a flow of nitrogen of about 50 mL/min using a heating rateof 5 K/min.

“Pharmaceutically acceptable” such as pharmaceutically acceptablecarrier, excipient, adjuvant, preservatives, solubilizers, stabilizers,wetting agents, emulsifiers, sweeteners, colorants, flavoring agents,salts for varying the osmotic pressure, buffers, masking agents orantioxidants, etc., means pharmacologically acceptable and substantiallynon-toxic to the subject to which the particular compound isadministered.

“Pharmaceutically acceptable” hence means substantially non-toxic to thesubject to which the pharmaceutically acceptable material isadministered.

A “cocrystal” is formed between a molecular or ionic API and a cocrystalformer that is a solid under ambient conditions, i.e. a cocrystal is amulti-component crystalline material comprising two or more solids (atambient conditions).

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

As already mentioned hereinabove, the present invention relates to fournovel crystalline forms and to an amorphous form of the followingcompound:

[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone

[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecan be isolated, depending upon the method of preparation, as form A, B,C or methylparaben cocrystal form and in an amorphous form.

Forms A, B and C can be isolated from several different crystallizationmethods of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneas described hereinafter.

The amorphous form can be obtained by lyophilization or fastconcentration of a[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonesolution as described hereinafter.

The methylparaben cocrystal form can be obtained by, digestion orre-crystallization of form A, B, C or amorphous form and methylparabenas described hereinafter.

In a certain embodiment of the invention, form A can be prepared bymethod comprising:

-   -   either recrystallization of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone        after seeding;    -   or recrystallization of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone        and spontaneous crystallization below about 40° C., without        seeding.

In a certain embodiment, form A can be obtained by recrystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonein ethanol at certain temperature and concentration after seeding withsubsequent crystallization during cooling. Form A can be obtainednormally by recrystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonein ethanol and spontaneous crystallization below 40° C., withoutseeding, with subsequent precipitation during cooling. However theformation of form A is not limited to ethanol, ethanol/water, methanol,methanol/water, toluene, 2-propanole, dioxane/water and dioxane.

These methods of preparation and in particular the preparation ofseeding crystals are further described in the examples hereinafter.

Form A is a solvent-free form as no significant weight loss is observedin the TGA curve prior to decomposition.

Form A can be characterized by at least three peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 13.1, 14.3, 15.4, 16.2,17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21.0, 22.6, 24.3.

Form A can be characterized by at least five peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 13.1, 14.3, 15.4, 16.2,17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21.0, 22.6, 24.3.

Form A can be characterized by at least seven peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 13.1, 14.3, 15.4, 16.2,17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21.0, 22.6, 24.3.

Form A can also be characterized by the following X-ray diffractionpeaks obtained with a CuKα radiation expressed in degrees 2Theta atapproximately: 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8,20.1, 20.4, 21.0, 22.6 and 24.3.

The term “approximately” means in this context that there is anuncertainty in the measurements of the degrees 2 Theta of ±0.2(expressed in degrees 2Theta). Form A can also be characterized by theX-ray diffraction pattern as substantially shown in FIG. 1.

Form A can also be characterized by an infrared spectrum having sharpbands at 3032, 1645, 1623, 1600, 1581, 1501, 1342, 1331, 1314, 1291,1266, 1245, 1154, 1130, 1088, 1054, 1012, 976, 951, 922, 889, 824, 787,758, 739, 714 and 636 cm⁻¹ (±3 cm⁻¹).

Form A can also be characterized by the infrared spectrum assubstantially shown in FIG. 2.

Form A can also be characterized by a melting point with onsettemperature (DSC) in the range of about 138° C. to 144° C.

These characteristics and others are shown in FIGS. 1 to 4.

A single crystal structure analysis of form A was conducted. Table 1lists the crystal structure data. The experimental XRPD patterncollected with the form A corresponds to the theoretical patterncalculated from crystal structure data. In the single crystal structureof form A the piperazine ring shows chair conformation with the pyridinesubstituent standing in equatorial position.

TABLE 1 Crystal structure data for form A crystal Name Form A EmpiricalFormula C₂₁ H₂₀ F₇ N₃ O₄ S Formula weight 543.46 Temperature 88 K Spacegroup P2(1)2(1)2 Unit cell dimensions a = 45.050(9) A alpha = 90 deg. B= 8.3500(17) A beta = 90 deg. C = 12.380(3) A gamma = 90 deg. Cellvolume 4657.0(16) A³ Molecules in unit cell 8 Calculated density 1.550g/cm³

In one embodiment of the invention, the compound[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprises at least 70% of a crystalline polymorph of form A as describedabove; in a certain embodiment, it comprises at least 90% of acrystalline polymorph of form A as described above; in a certainembodiment, it comprises at least 96% of a crystalline polymorph of formA as described above; in a certain embodiment, it comprises at least 99%of a crystalline polymorph of form A as described above.

In a certain embodiment of the invention, form B can be prepared by amethod comprising:

-   -   either seeding of a solution of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone;    -   or crystallization of a solution of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone        without seeding;    -   or recrystallization of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone        in one or more solvents and seeding with form B.

Form B can be obtained by seeding of an ethanol solution and subsequentcooling. Form B can be obtained occasionally without seeding of anethanol solution and subsequent cooling. Form B can also be prepared byre-crystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonein several solvents and seeding with form B.

Form B is a solvent-free form as no significant weight loss is observedin the TGA curve prior to decomposition.

These methods of preparation and in particular the preparation ofseeding crystals are further described in the examples hereinafter.

Form B can be characterized by at least three peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 11.4, 15.4, 16.2, 16.2,16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5, 26.4.

Form B can be characterized by at least five peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 11.4, 15.4, 16.2, 16.2,16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5, 26.4.

Form B can be characterized by at least seven peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 11.4, 15.4, 16.2, 16.2,16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5, 26.4.

Form B can also be characterized by the following X-ray diffractionpeaks obtained with a CuKα radiation expressed in degrees 2Theta atapproximately: 11.4, 15.4, 16.2, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1,21.0, 22.0, 22.5 and 26.4.

The term “approximately” means in this context that there is anuncertainty in the measurements of the degrees 2Theta of ±0.2 (expressedin degrees 2Theta).

Form B can also be characterized by the X-ray diffraction pattern assubstantially shown in FIG. 5.

Form B can also be characterized by an infrared spectrum having sharpbands at: 1644, 1635, 1621, 1599, 1567, 1514, 1488, 1398, 1343, 1328,1291, 1266, 1183, 1155, 1090, 1022, 1003, 973, 958, 938, 920, 897, 822,783, 753, 740, 683 and 638 cm⁻¹ (+3 cm⁻¹).

Form B can also be characterized by an infrared spectrum assubstantially shown in FIG. 6.

Form B can also be characterized by a melting point with onsettemperature (DSC) in the range of about 151° C. to 154° C.

These characteristics and others are shown in FIGS. 5 to 8.

A single crystal structure analysis of form B was conducted. Table 2lists the crystal structure data. The experimental XRPD patterncollected with the form B corresponds to the theoretical patterncalculated from crystal structure data. In the single crystal structureof form B the piperazine ring shows chair conformation with the pyridinesubstituent standing in axial position.

TABLE 2 Crystal structure data for the form B crystal Name Form BEmpirical Formula C₂₁ H₂₀ F₇ N₃ O₄ S Formula weight 543.46 Temperature88 K Space group P2(1) Unit cell dimensions A = 16.420(3) A alpha = 90deg. B = 6.1000(12) A beta = 106.49(3) deg. C = 23.750(5) A gamma = 90deg. Cell volume 2281.0(8) A³ Molecules in unit cell 4 Calculateddensity 1.583 g/cm³

In one embodiment of the invention, the compound[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprises at least 70% of a crystalline polymorph of form B as describedabove, in a certain embodiment, it comprises at least 90% of acrystalline polymorph of form B as described above; in a certainembodiment, it comprises at least 96% of a crystalline polymorph of formB as described above; in a certain embodiment, it comprises at least 99%of a crystalline polymorph of form B as described above.

In a certain embodiment of the invention, form C can be prepared by amethod comprising:

-   -   either crystallization of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone;    -   or by crystallization of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone        by seeding with form C;    -   or by tempering of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone        at about 150° C. and subsequent cooling.

Form C can be obtained by crystallization from a toluene ortoluene/n-heptane solution at 100° C. Form C can also be prepared bycrystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonein several solvents and seeding with form C.

Furthermore form C can be obtained by tempering of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneat 150° C. for 2 hours and subsequent rapid cooling.

These methods of preparation and in particular the preparation ofseeding crystals are further described in the examples hereinafter.

Form C is a solvent-free form as no significant weight loss is observedin the TGA curve prior to decomposition.

Form C can be characterized by at least three peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 14.9, 15.7, 16.7, 17.7,17.8, 18.7, 19.7, 21.8, 22.0, 25.2.

Form C can be characterized by at least five peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 14.9, 15.7, 16.7, 17.7,17.8, 18.7, 19.7, 21.8, 22.0, 25.2.

Form C can be characterized by at least seven peaks selected from thefollowing X-ray diffraction peaks obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 14.9, 15.7, 16.7, 17.7,17.8, 18.7, 19.7, 21.8, 22.0, 25.2.

Form C can also be characterized by the following X-ray diffractionpeaks obtained with a CuKα radiation expressed in degrees 2Theta atapproximately: 14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0 and25.2.

The term “approximately” means in this context that there is anuncertainty in the measurements of the degrees 2Theta of ±0.2 (expressedin degrees 2Theta).

Form C can also be characterized by the X-ray diffraction pattern assubstantially shown in FIG. 9.

Form C can also be characterized by an infrared spectrum having sharpbands at: 1641, 1622, 1601, 1581, 1566, 1514, 1398, 1378, 1341, 1322,1309, 1294, 1281, 1159, 1087, 1023, 1009, 966, 934, 917, 901, 822, 784,757, 681 and 640 cm⁻¹ (±3 cm⁻¹).

Form C can also be characterized by infrared spectrum as substantiallyshown in FIG. 10.

Form C can also be characterized by a melting point with onsettemperature (DSC) in the range of about 152° C. to 156° C.

These characteristics and others are shown in FIGS. 9 to 12.

In one embodiment of the invention, the compound[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprises at least 70% of a crystalline polymorph of form C as describedabove; in a certain embodiment, it comprises at least 90% of acrystalline polymorph of form C as described above; in a certainembodiment, it comprises at least 96% of a crystalline polymorph of formC as described above; in a certain embodiment, it comprises at least 99%of a crystalline polymorph of form C as described above.

In a certain embodiment of the invention, the amorphous form can beprepared by a method comprising:

-   -   either fast evaporation from a solution of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone        at about 40° C. under vacuum;    -   or lyophilization of a solution of a solution of        [4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

The amorphous form can be obtained from an ethanol solution upon fastevaporation at about 40° C. under vacuum. The amorphous form can also beobtained by lyophilization of a solution of 1.0 g of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonein 50 mL acetonitrile (condensator at −46° C. and vacuum at 0-1 mbar)

These methods of preparation of the amorphous form are further describedin the examples hereinafter.

The amorphous form can be characterized by the lack of sharp X-raydiffraction peaks in its XRPD pattern.

The amorphous form can also be characterized by the X-ray diffractionpattern as substantially shown in FIG. 13.

The amorphous form can be also be characterized by an infrared spectrumhaving sharp bands at 1642, 1622, 1599, 1579, 1509, 1487, 1399, 1329,1293, 1253, 1159, 1124, 1090, 1016, 960, 920, 903, 889, 827, 782, 763,739 and 636 cm⁻¹ (±3 cm⁻¹).

The amorphous form can also be characterized by infrared spectrum assubstantially shown in FIG. 14.

The amorphous form can be also be characterized by a glass transitiontemperature (DSC, heating rate 10 K/min, closed pan) of about 48° C. toabout 65° C. (The glass transition temperature is largely dependent onthe solvent/water content).

These characteristics and others are shown in FIGS. 13 to 17.

In one embodiment of the invention, the compound[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprises at least 70% of an amorphous form as described above; in acertain embodiment, it comprises at least 90% of an amorphous form asdescribed above; in a certain embodiment, it comprises at least 96% ofan amorphous form as described above; in a certain embodiment, itcomprises at least 99% of an amorphous form as described above.

In a certain embodiment of the invention, the methylparaben cocrystalform can be prepared by a method comprising re-crystallization of formA, B, C or amorphous form and methylparaben with or without seeding insolvent systems.

The methylparaben cocrystal form can be produced by digestion insolvents as e.g. ethanol and water. It can also be prepared byre-crystallization of form A, B, C or amorphous form and methylparabenwith or without seeding in solvent systems comprising but not limited toethanol.4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone-methylparabenratio can range from 1:1 to 1:10.

These methods of preparation and in particular the preparation ofseeding crystals are further elucidated in the examples hereinafter.

The methylparaben cocrystal form can be characterized by at least threepeaks selected from the following X-ray diffraction peaks obtained witha CuKα radiation expressed in degrees 2Theta at approximately: 8.0, 8.9,10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2, 25.9.

The methylparaben cocrystal form can be characterized by at least fivepeaks selected from the following X-ray diffraction peaks obtained witha CuKα radiation expressed in degrees 2Theta at approximately: 8.0, 8.9,10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2, 25.9.

The methylparaben cocrystal form can be characterized by at least sevenpeaks selected from the following X-ray diffraction peaks obtained witha CuKα radiation expressed in degrees 2Theta at approximately: 8.0, 8.9,10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2, 25.9.

The methylparaben cocrystal form can also be characterized by thefollowing X-ray diffraction pattern obtained with a CuKα radiationexpressed in degrees 2Theta at approximately: 8.0, 8.9, 10.5, 12.6,15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2 and 25.9.

The term “approximately” means in this context that there is anuncertainty in the measurements of the degrees 2Theta of ±0.2 (expressedin degrees 2Theta).

The methylparaben cocrystal form can also be characterized by the X-raydiffraction pattern as substantially shown in FIG. 18.

The methylparaben cocrystal form can also be characterized by aninfrared spectrum having sharp bands at 3154, 3081, 1709, 1614, 1586,1378, 1337, 1313, 1247, 1189, 1172, 1124, 1085, 1019, 959, 928, 916,908, 894, 857, 783, 772, 729 and 702 cm⁻¹ (±3 cm⁻¹).

The methylparaben cocrystal form can also be characterized by theinfrared spectrum as substantially shown in FIG. 19.

These characteristics and others are shown in FIGS. 18 to 21.

A single crystal structure analysis of the methylparaben cocrystal wasconducted. Table 3 lists the crystal structure data. The experimentalXRPD pattern collected with the methylparaben cocrystal corresponds tothe theoretical pattern calculated from crystal structure data.

TABLE 3 Crystal structure data for the methylparaben cocrystal form.Name methylparaben cocrystal form Empirical Formula C₂₉ H₂₈ F₇ N₃ O₇ SFormula weight 695.60 Temperature 89 K Space group P1 Unit celldimensions a = 10.140(2) A alpha = 83.65(3) deg. B = 11.690(2) A beta =79.88(3) deg. C = 13.870(3) A gamma = 72.75(3) deg. Cell volume1542.8(5) A³ Molecules in unit cell 2 Calculated density 1.497 g/cm³

In one embodiment of the invention, the compound comprises at least 70%of a methylparaben cocrystal of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneas described above; in a certain embodiment, it comprises at least 90%of a methylparaben cocrystal as described above; in a certainembodiment, it comprises at least 96% of a methylparaben cocrystal asdescribed above; in a certain embodiment, it comprises at least 99% of amethylparaben cocrystal as described above.

As mentioned hereinabove, in an aspect the invention relates to apharmaceutical composition comprising one or more of crystalline formsA, B, C or methylparaben cocrystal form or amorphous form as the activeingredient.

Pharmaceutical compositions according to the invention, in addition toone of the crystalline or amorphous forms according to the inventionmentioned hereinabove, can contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic and organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard shell capsules. Suitable carriers for softshell capsules are, for example, vegetable oils, waxes, fats, semi-solidand liquid polyols and the like. Depending on the nature of the activesubstance no carriers are, however, usually required in the case of softgelatine capsules. Suitable carriers for the solutions include, forexample, water, polyols, sucrose, invert sugar, glucose, and the like.

The active ingredient can be formulated at low or high concentrations ina composition further comprising usual pharmaceutically acceptableadjuvants known in the art.

These pharmaceutical compositions can be in the form of tablets, coatedtablets, dragées, hard and soft shell capsules, solutions, emulsions orsuspensions. The invention also provides a process for the production ofsuch compositions, which comprises bringing the aforementionedmodifications and forms into a galenical administration form togetherwith one or more therapeutically inert carriers.

In addition, the pharmaceutical compositions can containpharmaceutically acceptable preservatives, solubilizers, stabilizers,wetting agents, emulsifiers, sweeteners, colorants, flavoring agents,salts for varying the osmotic pressure, buffers, masking agents orantioxidants. They can also contain still other therapeutically valuablesubstances.

The dosage at which the active ingredient, i.e. the crystalline oramorphous forms according to the invention that can be administered canvary within wide limits and will, of course, have to be adjusted to theindividual requirements in each particular case. In the case of oraladministration the dosage for adults can vary from about 0.01 mg toabout 1000 mg, preferably from about 1 mg to about 240 mg, and stillmore preferably from about 3 mg to about 120 mg per day. The dailydosage may be administered as single dose or in divided doses and, inaddition, the upper limit can also be exceeded when this is found to beindicated.

The table hereinafter gives an example of a typical capsule formulationwhich can be prepared according to the invention.

Formulation Capsule Formulation Wet Granulation

TABLE 4 Capsule formulation composition mg/capsule 1.0 3.0 10.0 25.040.0 Item Ingredients mg mg mg mg mg 1. Form A of 1.00 3.00 10.00 25.0040.00 active ingredient 2. Lactose 114.00 112.00 105.00 90.00 75.00Monohydrate 3. Maize Starch 60.00 60.00 60.00 60.00 60.00 4. SodiumStarch 10.00 10.00 10.00 10.00 10.00 Glycolate 5. Povidone 30 10.0010.00 10.00 10.00 10.00 6. Talc 4.00 4.00 4.00 4.00 4.00 7. MagnesiumStearate 1.00 1.00 1.00 1.00 1.00 Total 200.00 200.00 200.00 200.00200.00

Manufacturing Procedure

1. Mix items 1, 2, 3, 4 and 5 in a suitable mixer.2. Granulate the mixed powder from step 1 with granulation liquid.3. Screen the mixture received from step 2, dry and sieve the granules.4. Add items 6 and 7 to the dried and sieved granules from step 3 andmix.5. Fill mixture from step 4 into a suitable capsule.

EXAMPLES Preparation of the Compounds According to the Invention Example1 Preparation of Form A General

Form A can be produced by digestion in solvents as e.g. methanol,ethanol, 2-propanol, isopropylacetate, t-butyl methyl ether, toluene orsolvent mixtures as acetone/water (e.g. 1:1, w/w), water/methanol (e.g.1:1, w/w), water/ethanol (e.g. 0.4:0.6, w/w). It can also be prepared byre-crystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-methanonewith or without seeding in solvent systems comprising but not limited toethanol, water/ethanol (e.g. 0.6:0.4, w/w).

Crystallization Procedure

30.0 g of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewere dissolved in 150 g ethanol and heated up to 70° C. The solution washot filtered. The temperature was reduced to 40-42° C. At 40-42° C. 300mg of form A seeding crystals of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewere added. The temperature was hold for 1 h at 40-42° C. Subsequentlythe suspension was cooled with 0.3 K/min down to 0 to −5° C. Afterstirring at 0 to −5° C. for 1 h the crystals were filtered, washed withca. 20 mL of ethanol (0 to −5° C.) and dried at 50° C./0-20 mbar for 14h. Yield: 26.31 g (87.7%).

Preparation of Seeding Crystals of Form A

Form A seeding crystals can be prepared by digestion of a slurry of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonein solvent systems comprising but not limited to ethanol, methanol andwater mixtures of ethanol/water (e.g. 0.4:0.6 w/w). After stirring theslurry at room temperature for several days form A crystals could befiltered and were dried at 50° C./0-20 mbar for 14 h. It might benecessary to repeat this procedure several times.

Solid State Properties of Form A

XRPD-pattern, IR-spectrum, DSC curve, and TG curve of form A are listedin FIGS. 1 to 4.

Example 2 Preparation of Form B General

Form B can be prepared by re-crystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewith or without seeding in different solvent systems comprisingmethanol, ethanol, 1,4-dioxane and water mixtures of these.

Crystallization Procedure

30.0 g of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewere dissolved in 150 g ethanol and heated up to 60° C. Dissolution of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneoccurred between 55-57° C. The solution was hot filtered. Thetemperature was reduced to 40-42° C. At 40-42° C. 3.0 g (10%-w) of formB seeding crystals of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewere added to the clear solution. Subsequently the suspension was cooleddown to 5° C. within 5 hours. The crystals were filtered, washed withca. 10 mL of ethanol (0° C.) and dried at 50° C./0-20 mbar for 14 h.Yield: 29.17 g (88.4%).

Preparation of Seeding Crystals of Form B

Form B seeding crystals can be prepared by rapid cooling of a highlysaturated solution of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonein solvent systems comprising but not limited to ethanol,tetrahydrofurane, toluene or 1,4-dioxane. 3.0 g of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewere dissolved in 9 g ethanol and heated up to 70° C. The solution washot filtered. The temperature of the clear solution was rapidly reducedto 0 to −5° C. The crystals were filtered, washed with ca. 20 mL ofethanol (0 to −5° C.) and dried at 50° C./0-20 mbar for 14 h. It mightbe necessary to repeat this procedure several times.

Solid State Properties of Form B

XRPD-pattern, IR-spectrum, DSC curve, and TG curve of form B are listedin FIGS. 5 to 8.

Example 3 Preparation of Form C General

Form C can be produced by digestion in solvents as n-heptane, toluene,o-xylene or solvent mixtures as n-heptane/toluene (e.g. 1:0.8, w/w). Itcan also be prepared by re-crystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewith seeding in different solvent systems.

Crystallization Procedure

45.0 g of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewere digested in 43.4 g toluene and 54.7 g n-heptane and heated up to98-100° C. The suspension was stirred at 98-100° C. for 48 h. Thesuspension was hot filtered. The obtained solid residues were dried at70° C./0-20 mbar for 24 h. Yield: 23.0 g (51:5%).

Solid State Properties of Form C

XRPD-pattern, IR-spectrum, DSC curve, and TG curve of form C are listedin FIGS. 9 to 12.

Example 4 Preparation of the Amorphous Form General

An amorphous form was accessible from ethanol solution upon fastevaporation at approx. 40° C. under vacuum. Further amorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewas accessible by lyophilization.

Preparation Procedure

0.50 g of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewere dissolved in 50 g of ethanol at 65° C. While spinning (rotaryevaporator) at 40° C. maximum vacuum was applied. After completeevaporation of the solvent, the solid was further dried at ca. 25°C./5-20 mbar for 18 h. Analysis revealed amorphous[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

Solid State Properties of the Amorphous Form

XRPD-pattern, IR-spectrum, DSC curve, and TG curve and moisturesorption/desorption isotherms of the amorphous form are listed in FIGS.13 to 17.

Example 5 Preparation of a Methylparaben Cocrystal Form General

Cocrystals of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneand methylparaben can be produced by digestion in solvents as e.g.ethanol and water. It can also be prepared by recrystallization of formA, B, C or amorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneand methylparaben with or without seeding in solvent systems comprisingbut not limited to ethanol. The[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone-methylparabenratio can range from 1:1 to 1:10.

Preparation Procedure

100 mg of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneand 28 mg methylparaben (1 part[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone+1part methylparaben) were dissolved in 0.3 mL ethanol and heated up todissolve both substances. The clear solution was cooled down to roomtemperature without stirring. After 7 weeks the crystals were filtered,washed with ethanol/water (60/40 w/w) and dried at room temperature/0-20mbar for 14 h.

Solid State Properties of the Methylparaben Cocrystal Form

XRPD-pattern, IR-spectrum, DSC curve, and TG curve of the methylparabencocrystal are listed in FIGS. 18 to 21.

1. A crystalline form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by at least three peaks selected from the following X-raydiffraction peaks obtained with a CuKα radiation, expressed in degrees2Theta 13.1, 14.3, 15.4, 16.2, 17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4,21.0, 22.6 and 24.3 (+0.2).
 2. A crystalline form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by the following X-ray diffraction peaks obtained with aCuKα radiation, expressed in degrees 2Theta=13.1, 14.3, 15.4, 16.2,17.1, 17.2, 17.6, 18.0, 19.8, 20.1, 20.4, 21.0, 22.6 and 24.3 (+0.2). 3.A crystalline form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by the X-ray diffraction pattern as substantially shown inFIG.
 1. 4. A crystalline form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by an infrared spectrum having sharp bands at 3032, 1645,1623, 1600, 1581, 1501, 1342, 1331, 1314, 1291, 1266, 1245, 1154, 1130,1088, 1054, 1012, 976, 951, 922, 889, 824, 787, 758, 739, 714 and 636cm⁻¹ (±3 cm⁻¹).
 5. A crystalline form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by an infrared spectrum as substantially shown on FIG. 2.6. A crystalline form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by at least three peaks selected from the following X-raydiffraction peaks obtained with a CuKα radiation, expressed in degrees2Theta=11.4, 15.4, 16.2, 16.4, 17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5,26.4 (±0.2).
 7. A crystalline form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by the following X-ray diffraction peaks obtained with aCuKα radiation, expressed in degrees 2Theta=11.4, 15.4, 16.2, 16.4,17.8, 18.3, 19.2, 20.1, 21.0, 22.0, 22.5 and 26.4 (±0.2).
 8. Acrystalline form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by the X-ray diffraction pattern as substantially shown inFIG.
 5. 9. A crystalline form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by an infrared spectrum having sharp bands at 1644, 1635,1621, 1599, 1567, 1514, 1488, 1398, 1343, 1328, 1291, 1266, 1183, 1155,1090, 1022, 1003, 973, 958, 938, 920, 897, 822, 783, 753, 740, 683 and,638 cm⁻¹ (±3 cm⁻¹).
 10. A crystalline form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by an infrared spectrum as substantially shown in FIG. 6.11. A crystalline form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by at least three peaks selected from the following X-raydiffraction peaks obtained with a CuKα radiation, expressed in degrees2Theta=14.9, 15.7, 16.7, 17.7, 17.8, 18.7, 19.7, 21.8, 22.0 and 25.2(+0.2).
 12. A crystalline form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by the following X-ray diffraction peaks obtained with aCuKα radiation, expressed in degrees 2Theta=14.9, 15.7, 16.7, 17.7,17.8, 18.7, 19.7, 21.8, 22.0 and 25.2 (+0.2).
 13. A crystalline form Cof[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by the X-ray diffraction pattern as substantially shown inFIG.
 9. 14. A crystalline form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by an infrared spectrum having sharp bands at 1641, 1622,1601, 1581, 1566, 1514, 1398, 1378, 1341, 1322, 1309, 1294, 1281, 1159,1087, 1023, 1009, 966, 934, 917, 901, 822, 784, 757, 681 and 640 cm⁻¹(±3 cm⁻¹).
 15. A crystalline form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by the infrared spectrum as substantially shown in FIG.10.
 16. An amorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by an absence of sharp X-ray peaks in its XRPD patternand/or by an infrared spectrum having sharp bands at 1642, 1622, 1599,1579, 1509, 1487, 1399, 1329, 1293, 1253, 1159, 1124, 1090, 1016, 960,920, 903, 889, 827, 782, 763, 739 and 636 cm⁻¹ (+3 cm⁻¹).
 17. Anamorphous form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecharacterized by a glass transition temperature (DSC, heating rate 10K/min, dosed pan) of about 48° C. to about 65° C.
 18. A methylparabencocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-methanonecharacterized by at least three peaks selected from the following k-raydiffraction peaks obtained with a CuKα radiation, expressed in degrees2Theta=8.0, 8.9, 10.5, 12.6, 15.2, 16.1, 17.7, 18.5, 19.8, 20.2, 21.7,22.9, 24.2 and 25.9 (+0.2).
 19. A methylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-methanonecharacterized by the following X-ray diffraction peaks obtained with aCuKα radiation, expressed in degrees 2Theta=8.0, 8.9, 10.5, 12.6, 15.2,16.1, 17.7, 18.5, 19.8, 20.2, 21.7, 22.9, 24.2 and 25.9 (±0.2).
 20. Amethylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-methanonecharacterized by the X-ray diffraction pattern as substantially shown inFIG.
 18. 21. A methylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-methanonecharacterized by an infrared spectrum having sharp bands at 3154, 3081,1709, 1614, 1586, 1378, 1337, 1313, 1247, 1189, 1172, 1124, 1085, 1019,959, 928, 916, 908, 894, 857, 783, 772, 729 and 702 cm⁻¹ (±3 cm⁻¹). 22.A methylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-methanonecharacterized by an infrared spectrum as substantially shown in FIG. 19.23. A method for preparing a crystalline form A of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprising: either recrystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneafter seeding; or recrystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneand spontaneous crystallization below about 40° C., without seeding. 24.A method for preparing a crystalline form B of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprising: either seeding of a solution of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone;or crystallization of a solution of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonewithout seeding; or recrystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonein one or more solvents and seeding with form B.
 25. A method forpreparing a crystalline form C of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprising: either crystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone;or by crystallization of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneby seeding with form C; or by tempering of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneat about 150° C. and cooling.
 26. A method for preparing an amorphousform of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprising: either fast evaporation from a solution of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanoneat about 40° C. under vacuum; or lyophilization of a solution of asolution of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin--1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.27. A method for preparing methylparaben cocrystal form of[4-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanonecomprising: either digestion in solvents; or recrystallization of formA, B, C or amorphous form and Methyl-paraben with or without seeding insolvent systems.
 28. A pharmaceutical composition comprising acrystalline form A, B, C or an amorphous form or a methylparabencocrystal form of[4-(3-Fluoro-5-trifluoromethylpyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-methanoneas an active ingredient.